A quinazolinone derivative and its use in medicine

Abstract

The present application relates to a quinazolinone derivative represented by general formula (I) and its medical application, in particular to a quinazolinone derivative represented by general formula (I) or its stereoisomer, a pharmaceutical composition containing the same, and the use of the quinazolinone derivative or the pharmaceutical composition of the present application in the preparation of an antitumor drug.

Description

TECHNICAL FIELD

[0001] The present application relates to a quinazolinone derivative or a stereoisomer thereof and its use in medicine. BACKGROUND

[0002] PARPs (poly(ADP-ribose) polymerases) are a class of poly-ADP-ribose polymerases that catalyze the poly-ADP-ribosylation of various proteins, which plays an important role in many cellular processes such as DNA damage repair, transcription regulation, chromatin recombination and remodeling. At present, although a number of PARP1 / 2 inhibitors have been successfully marketed, there are still common side effects such as blood and gastrointestinal tract in clinical use, whether used alone or in combination, which limits the clinical application. Therefore, the development of safer and more effective PARP inhibitors is still a problem that needs to be solved in clinical practice. A series of studies have shown that, compared with PARP1 / 2 inhibitors, highly selective PARP1 inhibitors have better efficacy and lower toxicity, which is expected to reduce the potential risks of current PARP drugs in clinical practice, expand the range of clinical application, and improve the quality of life of patients. SUMMARY

[0003] The purpose of the present application is to provide a quinazolinone derivative or a stereoisomer thereof, a pharmaceutical composition thereof, and its use in medicine.

[0004] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof:

[0005]

[0006] wherein:

[0007] R1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S;

[0008] X is selected from N or C(R x );

[0009] Y is selected from C(R y ) or N;

[0010] Z is selected from C(R z ) or N;

[0011] R x , Ry , R z each independently selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S;

[0012] R2is selected from cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl or C(=O)NH(R3), said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S;

[0013] R3is selected from C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl is optionally further substituted by 1 or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S;

[0014] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof:

[0015] X is selected from N or C(R x ); R x is selected from C 1-6 alkyl or halogen;

[0016] and when X is N, R3cannot be C 1-6 alkyl.

[0017] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof:

[0018] R2is selected from cyano or C(=O)NH(R3);

[0019] R3is selected from C 1-6 alkyl, C1-6 alkyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; said C 1-6 alkyl, C 1-6 alkyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S.

[0020] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof, wherein:

[0021] Y is selected from C(R y ) or N; R y is selected from H or C 1-6 alkyl or halogen.

[0022] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof, wherein:

[0023] Z is selected from C(H) or N.

[0024] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof, wherein:

[0025] R1is selected from C 1-4 alkyl.

[0026] One or more embodiments of the present application provide a compound of general formula (I), or a stereoisomer thereof, wherein:

[0027] R4is selected from halogen or C 1-6 alkyl.

[0028] In one or more embodiments of the present application, the compound of the present application is selected from:

[0029]

[0030] One or more embodiments of the present application provide a pharmaceutical composition comprising:

[0031] (1) a compound of the present application or a stereoisomer thereof;

[0032] (2) optionally one or more other active ingredients; and

[0033] (3) a pharmaceutically acceptable carrier and / or excipient.

[0034] One or more embodiments of the present application provide use of a compound of the present application or a stereoisomer thereof or a pharmaceutical composition of the present application in the manufacture of a medicament for treating cancer.

[0035] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0036] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present application include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br.

[0037] "Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, neopentyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, and various branched isomers thereof; when substituted with a substituent group, can be optionally further substituted with one or more substituent groups.

[0038] "Alkoxy" refers to a group formed by replacing at least one carbon atom of an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy. The definition of the alkyl group is the same as that described above for "alkyl".

[0039] "Cycloalkyl" means a saturated cyclic hydrocarbon group, which ring can be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 20 membered polycyclic ring system, with the ring carbon atoms preferably being 3 to 10 carbon atoms, and further preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cycloheptatrienyl. When substituted, the "cycloalkyl" group can be optionally further substituted with 0 or more substituents.

[0040] "Heterocycloalkyl" means a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O, or S, preferably a 3 to 8 membered heterocycloalkyl group. The optionally substituted N, S in the "heterocycloalkyl" ring can be oxidized to various oxidation states; the "heterocycloalkyl" group can be attached to a heteroatom or carbon atom; the "heterocycloalkyl" group can be a bridged ring or spirocyclic. Non-limiting examples of "heterocycloalkyl" groups include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, and oxaspiro[3.3]heptanyl.

[0041] "Alkenyl" means a straight or branched chain unsaturated aliphatic hydrocarbon group containing 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, and further more preferably 2 to 6 carbon atoms. Non-limiting examples include ethenyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group can be optionally further substituted with 1 or more substituents.

[0042] "Alkynyl" refers to a straight chain or branched chain unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyn-l-yl, pentyn-2-yl, hexyn-l-yl, 1-heptynyl-l-yl, heptynyl-3-yl, heptynyl-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group can be optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, alkyl, alkoxy, straight chain alkenyl, straight chain alkynyl, amino, nitro, cyano, thiol, amido, carbocyclyl, or heterocyclyl.

[0043] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated aromatic or non-aromatic ring, which when aromatic is defined the same as "heteroaryl" above; which when non-aromatic can be a monocyclic, bicyclic, or tricyclic ring system containing 3 to 10 members (e.g., 3, 4, 5, 6, 7, 8, 9, 10 members), 4 to 12 members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 members), or 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15 members), and containing 1 to 4 heteroatoms (e.g., 1, 2, 3, 4) selected from N, O, or S, preferably 3 to 8 membered heterocyclyl. Optionally 1 to 4 (e.g., 1, 2, 3, 4) N, S in the ring of the "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclyl" or "heterocycle" can be attached at a heteroatom or carbon atom; the "heterocyclyl" or "heterocycle" can be fused, bridged, or spiro. The "heterocyclyl" or "heterocycle" can be optionally further substituted with one or more substituents.

[0044] When "alkyl", "alkoxy", "alkenyl", "alkynyl", "heterocyclyl", "heterocycle", "cycloalkyl", or "heterocycloalkyl" as described above are substituted, they can be optionally further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from F, Cl, Br, I, hydroxyl, thiol, nitro, cyano, amino, C 1-6 alkylamino, =O, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4 R q5 , =NR q6 , -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6alkyl, -C(=O)NR q4 R q5 , C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 aryl, -OC(=O)C 6-10 aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 heterocycloalkyl, -C(=O)OC 3-8 heterocycloalkyl, -OC(=O)C 3-8 cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 heterocycloalkyl, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6 alkynyl, and wherein said substituents of the alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 heterocycloalkyl or -NHC(=O)C 3-8 cycloalkyl is optionally further substituted with one to three substituents selected from the group consisting of OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4 R q5 or =O; R q1 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy or C 6-10 aryl; R q2 , R q3 is selected from the group consisting of H or C 1-6 alkyl; R q4 , Rq5 H, C 1-6 alkyl, -NH(C=NR q1 )NR q2 R q3 , -S(=O)2NR q2 R q3 , -C(=O)R q1 or -C(=O)NR q2 R q3 wherein said C 1-6 alkyl is optionally further substituted with one or more substituents selected from OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 and R q5 form a 3- to 8-membered heterocyclic ring with the N atom, said ring can contain one or more heteroatoms selected from N, O or S.

[0045] "Pharmaceutical composition" refers to a mixture of one or more compounds of the application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as carriers, excipients or stabilizers.

[0046] "Carrier" refers to a material, such as a liquid or solid, which does not itself induce the production of antibodies to it, and it is not deleterious or harmful when administered to an animal.

[0047] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration to an animal. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose and its derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, lubricants, and disintegrating agents.

[0048] "Stereoisomers" refers to isomers that have the same molecular formula but different structures, resulting from the spatial arrangement of the atoms. Stereoisomers include enantiomers (mirror image isomers) and diastereomers (isomers that are not mirror images of one another).

[0049] "Optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl. DETAILED DESCRIPTION

[0050] The following examples illustrate the technical solutions of the present application, but the protection scope of the present application includes but is not limited to the following.

[0051] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by a Bruker Avance III 400 and a Bruker Avance 300 nuclear magnetic instrument, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0052] The MS is measured by Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0053] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4mm-0.5mm;

[0054] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0055] Example 1

[0056] 5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0057] 5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0058]

[0059] First step

[0060] 5-bromo-3-methylbenzene-1,2-diamine

[0061] 5-bromo-3-methylbenzene-1,2-diamine

[0062] Compound 1a (5 g, 21.6 mmol) was dissolved in 200 mL of 1,4-dioxane solution, sodium hydrogen carbonate (8.3 g, 99.4 mmol) and sodium hydrosulfite (26 g, 149 mmol) dissolved in 100 mL of water were added, the reaction was stirred at room temperature for 2 hours, 200 mL of ethyl acetate and 100 mL of sodium bicarbonate aqueous solution were added and extracted, the organic phase was collected, anhydrous sodium sulfate was dried, and the solvent was removed by rotary evaporation to obtain compound 1b (yellow solid, 4.2 g, yield 96.7%).

[0063] LCMS m / s = 202.07 [M+1].

[0064] Second step:

[0065] 7-bromo-3-ethyl-5-methylquinoxalin-2(1H)-one

[0066] 7-bromo-3-ethyl-5-methylquinoxalin-2(1H)-one

[0067] Compound 1b (2 g, 10.0 mmol) was dissolved in 100 mL of toluene, 2-oxobutyric acid methyl ester compound (1.4 g, 11.2 mmol) was added, and the reaction was heated at 100°C for 2 hours, filtered, the filter cake was collected, and the filter cake was washed with petroleum ether (50 mL) three times to obtain compound 1c (white solid, 910 mg, yield 34.1%).

[0068] LCMS m / s = 268.1 [M+1].

[0069] Third step:

[0070] 3-ethyl-7-(hydroxymethyl)-5-methylquinoxalin-2(1H)-one

[0071] 3-ethyl-7-(hydroxymethyl)-5-methylquinoxalin-2(1H)-one

[0072] Compound 1c (500 mg, 1.87 mmol) was dissolved in 10 mL of 1,4-dioxane solution, tetrakis triphenylphosphine palladium (280 mg, 0.24 mmol) and (tributyltin) methanol (1.2 g, 3.74 mmol) were added, and the reaction was heated at 100°C for 8 hours under nitrogen protection, the solvent was removed by rotary evaporation, and medium pressure preparative separation was performed to obtain compound 1d (white solid, 207 mg, yield 40%).

[0073] 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.10 (d, 1H), 7.05 (s, 1H), 5.35 (s, 1H), 4.53 (s, 2H), 2.79 (q, 2H), 2.55 (s, 3H), 1.23 (t, 3H).

[0074] LCMS m / s = 219.26 [M+1].

[0075] Fourth Step:

[0076] 7-(Bromomethyl)-3-ethyl-5-methylquinoxalin-2(lH)-one le

[0077] 7-(Bromomethyl)-3-ethyl-5-methylquinoxalin-2(lH)-one le

[0078] Compound Id (100 mg, 0.35 mmol) was dissolved in 2 mL of 33% hydrobromic acid in acetic acid and heated at 80 °C for 1 h. The solvent was removed by rotary evaporation to obtain compound le as a crude (yellow solid, 100 mg).

[0079] LCMS m / s = 282.15 [M+1].

[0080] Fifth Step:

[0081] 5-(4-((2-Ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-l-yl)-N- methylpicolinamide Compound 1

[0082] 5-(4-((2-Ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-l-yl)-N- methylpicolinamide Compound 1

[0083] Compound le (100 mg, 0.35 mmol) was dissolved in 3 mL of N-methyl pyrrolidine, compound If (92 mg, 0.42 mmol) and N,N-diisopropylethylamine (226 mg, 1.75 mmol) were added and heated at 80 °C for 4 h. The reaction was dried by rotary evaporation and compound 1 was isolated by preparative separation as a white solid (42 mg, 28% yield).

[0084] 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.39 (dd, 1H), 7.11 (s, 2H), 3.55 (s, 2H), 3.27 (s, 4H), 2.81 (t, 2H), 2.78 (d, 3H), 2.57 (s, 3H), 2.54 (t, 4H), 1.23 (t, 3H).

[0085] LCMS m / s = 421.52 [M+1].

[0086] Example 2

[0087] 5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinonitrile

[0088] 5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinonitrile

[0089]

[0090]

[0091] Compound 2 was prepared according to the procedure of compound 1 (white solid, 14 mg, yield 32%).

[0092] 1 H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 7.83 (d, 1H), 7.39 (dd, 1H), 7.11 (s, 2H), 3.55 (s, 2H), 3.27 (s, 4H), 2.81 (t, 2H), 2.78 (d, 3H), 2.57 (s, 3H), 2.54 (t, 4H), 1.23 (t, 3H).

[0093] LCMS m / s = 421.52 [M+1].

[0094] Example 3

[0095] 5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinonitrile

[0096] 5-(4-((8-chloro-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpicolinamide

[0097]

[0098] Compound 3 was prepared according to the procedure of Compound 1 (white solid, 29 mg, 46% yield).

[0099] 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.42 (d, 1H), 7.81 (d, 1H), 7.43-7.25 (m, 3H), 7.18 (q, 1H), 3.56 (s, 2H), 3.41 (t, 4H), 2.82 (t, 2H), 2.69 (t, 2H), 2.58 (s, 3H), 2.51 (dd, 2H), 1.24 (t, 3H).

[0100] LCMS m / s = 441.2 [M+1].

[0101] Example 4

[0102] (R)-5-(4-((8-chloro-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide Compound 4

[0103] (R)-5-(4-((8-chloro-2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0104]

[0105] Compound 4 was prepared according to the procedure of Compound 1 (white solid, 20 mg, 37% yield).

[0106] 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.39 (d,, 1H), 7.61 (s, 1H), 7.45 (t, 1H), 6.81-6.78 (m, 2H), 4.40 (d, 1H), 3.81 (td, 2H), 3.73-3.66 (m, 1H), 3.64 (s, 2H), 3.53 (dd, 1H), 3.28 (s, 4H), 2.71-2.54 (m, 6H), 2.47 (s, 3H), 2.17-2.06 (m, 1H), 1.87 (dd, 1H), 1.18 (t, 3H).

[0107] LCMS m / s = 511.1 [M+l].

[0108] Example 5

[0109] (R)-4-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0110] (R)-4-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-3-fluoro-N-(tetrahydrofuran-3-yl)benzamide

[0111]

[0112] Compound 5 was prepared according to the procedure for Compound 1 (white solid, 22 mg, yield 37%).

[0113] 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.39 (d,, 1H), 7.61 (s, 1H), 7.45 (t, 1H), 6.81-6.78 (m, 2H), 4.40 (d, 1H), 3.81 (td, 2H), 3.73-3.66 (m, 1H), 3.64 (s, 2H), 3.53 (dd, 1H), 3.28 (s, 4H), 2.71-2.54 (m, 6H), 2.47 (s, 3H), 2.17-2.06 (m, 1H), 1.87 (dd, 1H), 1.18 (t, 3H).

[0114] LCMS m / s = 494.2 [M+l].

[0115] Example 6

[0116] (R)-5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0117] (R)-5-(4-((2-ethyl-8-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide

[0118]

[0119] Compound 6 was prepared according to the procedure of Compound 1 (white solid, 21 mg, yield 39%).

[0120] 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.42 (d, 1H), 7.60 (s, 1H), 7.42 (t, 1H), 6.88-6.82 (m, 2H), 4.38 (d, 1H), 3.80 (td, 2H), 3.76 (t, 1H), 3.64 (s, 2H), 3.51 (dd, 1H), 3.23 (s, 4H), 2.71-2.58 (m, 6H), 2.46 (s, 3H), 2.31 (s, 3H), 2.16-2.11 (m, 1H), 1.85 (dd, 1H), 1.18 (t, 3H).

[0121] LCMS m / s = 491.2 [M+1].

[0122] Biological test

[0123] 1. PARP1, PARP2 activity inhibition test

[0124] The inhibitory activity of the compound on PARP1 and PARP2 was detected by PARP1 Chemiluminescent assay (purchased from BPS Bioscience, Cat No: 80551) and PARP2 Chemiluminescent assay (purchased from BPS Bioscience, Cat No: 80552), respectively. The results were quantified by chemiluminescence, and the specific experimental procedure was as follows:

[0125] (1) The 96-well plate was coated overnight using 1x histone mixture (50 μL / well);

[0126] (2) Discard the blocking buffer; add Blocking buffer 3 (200 μL) to each well, and incubate at room temperature for 90 minutes;

[0127] (3) Discard the blocking buffer, and wash twice with PBST; add 25 μL of main mixture (containing 2.5 μL of 10xPARP buffer, 2.5 μL of 10xPARP Assay mixture, 5 μL of activated DNA, 15 μL of ddH2O), 5 μL of inhibitor (the initial concentration of the inhibitor is 10 μM, and 8 concentrations are diluted at a ratio of 1:5), 20 μL of enzyme (2 ng / μL); incubate at room temperature for 1 hour;

[0128] (4) Discard the liquid, and wash twice with PBST; add Streptavidin-HRP (diluted 50 times with Blocking buffer 3) 50 μL; incubate at room temperature for 30 minutes;

[0129] (5) Discard the liquid, and wash three times with PBST; add 100 μL of ELISA ECL Substrate A / B mix (50 μL each);

[0130] (6) Detect the results by using an enzyme label instrument, and calculate IC50 by using GraphPad Prism 8.

[0131] Compound No. PARP1 IC50 (pM) PARP2 IC50 (pM) Compound 1 <1 <10 Compound 2 <1 <10

[0132] The results show that the compound has significant inhibitory activity on PARP1, and has good selectivity relative to PARP2.

[0133] 2. MDA-MB-436 cell proliferation inhibition experiment

[0134] MDA-MB-436 cells (supplier: ATCC) are cultured in DMEM medium (10% FBS, 1% PS), and the culture condition is 37℃, 5% CO2. When the cells grow to the logarithmic growth phase, the cells are resuspended and diluted to 1500 cells / ml with DMEM medium. 40 μL of the test compound (final concentrations are 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, 0.00512 nM) is added to each well of a 384-well plate; 2 repeats are made for each concentration gradient, and control group 1 (0.1% DMSO is added) and control group 2 (blank medium) are set. Then, 40 μL of cell suspension is added to the 384-well plate (no cells are added to control group 2).

[0135] The 384-well plate was continuously cultured in an incubator (37℃, 5% CO2) for 7 days, and then the 384-well plate was taken out and placed at room temperature for 30 minutes. 30 μL of Celltiter Glo assay kit detection solution was added to each well, and the plate was shaken for 3 minutes, and then placed at room temperature for 30 minutes. Chemiluminescence values were measured by a microplate reader (PerkinElmer; EnVision).

[0136] The detection results were curve-fitted and IC50 was calculated by GraphPad Prism 8.

[0137] Compound No. MDA-MB-436 cell IC50 (pM) Compound 1 <1

[0138] The results show that the compound has obvious inhibitory effect on the proliferation of MDA-MB-436 cells.

[0139] The specific embodiments are described in detail in the specification of the present application, and those skilled in the art should recognize that the above-mentioned embodiments are exemplary and cannot be understood as limiting the present application. For those skilled in the art, a number of improvements and modifications can be made to the present application without departing from the principles of the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A quinazolinone derivative of the general formula (I) ###0001### and stereoisomers thereof, wherein: R1 is selected from the group consisting of H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkylsulfonylamino, C1-6 alkylsulfinylamino, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C1-6 alkoxycarbonyloxy, C1-6 alkylcarbonyloxy, C1-6 alkylcarbonylamino, C1-6 alkylcarbonylaminocarbonyl, C1-6 alkylcarbonylaminosulfonyl, C1-6 alkylcarbonylaminosulfinyl, C1-6 alkylcarbonylaminosulfonyloxy, C1-6 alkylcarbonylaminosulfinylamino, C1-6 alkylcarbonylaminosulfonylamino, C1-6 alkylcarbonylaminosulfonylaminocarbonyl, C1-6 alkylcarbonylaminosulfonylaminosulfonyl, C1-6 alkylcarbonylaminosulfonylaminosulfinyl, C1-6 alkylcarbonylaminosulfonylaminosulfonyloxy, C1-6 alkylcarbonylaminosulfonylaminosulfinylamino, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminocarbonyl, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfonyl, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfinyl, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfonyloxy, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfinylamino, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfonylaminocarbonyl, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfonylaminosulfonyl, C1-6 alkylcarbonylaminosulfonylaminosulfonylaminosulfonylaminosulfonyloxy, C1-6 alkylcarbonylaminosulfony ​ R1is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, said C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S; X is selected from N or C(R x ); R x is selected from C 1-6 alkyl or halogen; and when X is N, R3cannot be C 1-6 alkyl; Y is selected from C(R y ) or N; Z is selected from C(R z ) or N; R y , R z each independently is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, which C 3-8 heterocycloalkyl can contain 1 to 4 heteroatoms selected from N, O or S; ​ ​ ​ Y is selected from C(R y ) or N; R y is selected from H or C 1-6 alkyl or halogen. ​ ​ ​ R1is selected from C 1-4 alkyl. ​ ​ ​ ​ ​ ​ ​

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